Affinage

RAB21

Ras-related protein Rab-21 · UniProt Q9UL25

Length
225 aa
Mass
24.3 kDa
Annotated
2026-06-10
44 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAB21 is a small GTPase of the early endocytic pathway that cycles between GDP- and GTP-bound states to control the internalization, sorting, and recycling of plasma-membrane cargo (PMID:15561770). It localizes to EEA1-, transferrin-receptor-, and Rab5-positive early endosomes, where GTP-hydrolysis-deficient (Q78L) and GDP-locked (T33N) mutants reveal opposing effects on endosome morphology and ligand trafficking (PMID:15561770). Its nucleotide cycle is driven by distinct GEFs—Varp/VARP, which preferentially activates GDP-bound RAB21 over Rab5 (PMID:16525121), and the myotubularin pseudophosphatase Sbf/MTMR13, which couples PI(3)P turnover to RAB21 activation (PMID:22648168, PMID:25648148). A central function is the trafficking of alpha-integrins: RAB21 binds directly to the integrin alpha-subunit cytoplasmic domain to govern integrin endo/exocytosis, adhesion, and migration (PMID:16754960), with p120RasGAP (RASA1) competing for the same binding site to promote integrin recycling (PMID:21768288), and this integrin trafficking to the cleavage furrow is required for cytokinesis (PMID:18804435). Beyond integrins, RAB21 directs cargo-specific endosomal fates: it promotes EGFR internalization and degradation to attenuate MAPK signaling (PMID:22525675), drives retromer/SNX27-dependent recycling of the glucose transporter SLC2A1/GLUT1 away from lysosomal mis-sorting (PMID:35993307), controls caveolin-1-dependent endocytosis governing neurite pruning (PMID:36683567) and surface levels of APP during cortical migration (PMID:37534523), facilitates LPS-induced endosomal trafficking of TLR4 to sustain pro-inflammatory signaling (PMID:30471852), and broadly regulates the macrophage surfaceome including FcγR-dependent phagocytosis (PMID:40580479). RAB21 also acts in autophagy, where MTMR13-driven activation promotes VAMP8 endolysosomal trafficking for autophagosome-lysosome fusion (PMID:25648148) and a VARP-RAB21-VAMP7 axis mediates autophagic ATP secretion (PMID:40395984). In neutrophils, PKN1-mediated phosphorylation of RPH3A enhances RPH3A binding to GTP-bound RAB21 to drive polarized integrin activation and adhesion (PMID:28636945).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2004 High

    Established RAB21's steady-state compartment and its requirement for endocytic flux, defining it as an early-endosome GTPase whose nucleotide state shapes endosome morphology.

    Evidence GFP-fusion confocal and EM imaging with GTP/GDP mutants and transferrin/EGF endocytosis assays

    PMID:15561770

    Open questions at the time
    • Did not identify cargo bound directly by RAB21
    • GEF/GAP regulators unknown at this stage
  2. 2006 High

    Identified the first direct RAB21 cargo interaction, linking the GTPase to integrin trafficking and cell adhesion/motility.

    Evidence Reciprocal Co-IP, siRNA, overexpression, integrin point-mutant rescue, adhesion and migration assays

    PMID:16754960

    Open questions at the time
    • Whether binding is direct or bridged by an adaptor not fully resolved
    • Recycling versus degradation fate of integrins not defined here
  3. 2006 High

    Defined Varp as a RAB21-selective GEF, providing the molecular activation switch for the GTPase at endosomes.

    Evidence In vitro nucleotide exchange assay, GDP/GTP-mutant Co-IP, RNAi, domain mutagenesis, confocal microscopy

    PMID:16525121

    Open questions at the time
    • RAB21 GAP not identified
    • Physiological cargo activated downstream of Varp-RAB21 not addressed
  4. 2008 High

    Showed that RAB21-dependent integrin trafficking to the cleavage furrow is required for cytokinesis, connecting endosomal trafficking to genome stability and cancer.

    Evidence siRNA, dominant-negative/constitutively-active and integrin-binding mutants, live imaging, rescue, cancer cell line analysis

    PMID:18804435

    Open questions at the time
    • Mechanism of furrow-directed delivery not molecularly detailed
    • Which integrin species are essential at the furrow not specified
  5. 2009 High

    Extended Varp-RAB21 GEF function to a neuronal effector axis, linking RAB21 activation to VAMP7-dependent membrane delivery for neurite growth.

    Evidence Co-IP, RNAi, dominant-negative/CA mutants, confocal co-localization, neurite growth assays in hippocampal neurons

    PMID:19745841

    Open questions at the time
    • Direct RAB21-VAMP7 versus Varp-bridged interaction not separated
    • Cargo delivered to growing neurites unidentified
  6. 2011 High

    Resolved how endocytosed integrins exit RAB21 endosomes by demonstrating p120RasGAP competes with RAB21 for the integrin tail to drive recycling.

    Evidence Co-IP, siRNA, integrin recycling and motility assays

    PMID:21768288

    Open questions at the time
    • Spatiotemporal switch between RAB21 and p120RasGAP binding not directly imaged
    • RAB21 GAP for the cycle not identified
  7. 2012 High

    Identified a second GEF class (Sbf/MTM) coupling PI(3)P turnover to RAB21 activation in macrophage remodeling, linking lipid signaling to RAB21.

    Evidence GEF assay, RNAi, genetic epistasis, live imaging, PI(3)P biosensors, Co-IP in Drosophila macrophages

    PMID:22648168

    Open questions at the time
    • Mammalian conservation not yet demonstrated at this step
    • Effector executing protrusion control not defined
  8. 2012 Medium

    Placed RAB21 upstream of receptor tyrosine kinase signaling by showing it drives EGFR internalization and degradation to dampen MAPK output.

    Evidence Co-IP, overexpression, EGFR degradation and MAPK western blots in HEK293T/HeLa

    PMID:22525675

    Open questions at the time
    • Single Co-IP, overexpression-based functional readouts
    • Endogenous loss-of-function effect on EGFR not tested
  9. 2015 High

    Defined a starvation-responsive MTMR13-RAB21-VAMP8 axis required for autophagosome-lysosome fusion, integrating RAB21 into autophagy.

    Evidence RNAi, RAB21 activity pulldown, Co-IP, endolysosomal trafficking and autophagy flux assays

    PMID:25648148

    Open questions at the time
    • Direct RAB21-VAMP8 binding versus indirect trafficking not separated
    • Signal activating MTMR13 GEF activity upon starvation not defined
  10. 2017 High

    Uncovered phosphoregulation of a RAB21 effector, showing PKN1-phosphorylated RPH3A binds RAB21-GTP to polarize neutrophil integrin activation in vivo.

    Evidence Kinase assay, Co-IP, myeloid-specific PKN1 KO, neutrophil adhesion/migration, renal ischemia-reperfusion model

    PMID:28636945

    Open questions at the time
    • How RPH3A binding spatially restricts RAB21 not fully resolved
    • Direct RAB21 contribution separable from RPH3A not isolated
  11. 2017 High

    Linked RAB21 to amyloidogenesis by showing it promotes PS1/gamma-secretase endosomal relocalization to modulate Abeta generation.

    Evidence Co-IP/MS, reciprocal Co-IP, IF, overexpression/siRNA, Abeta ELISA, secretase activity assays, fractionation

    PMID:28547526

    Open questions at the time
    • Whether PS1 is a direct RAB21 cargo or co-trafficked passenger unresolved
    • Disease relevance beyond cell models not established
  12. 2018 Medium

    Connected RAB21 to innate immune signaling by showing it mediates LPS-induced TLR4 endosomal trafficking and downstream cytokine production.

    Evidence Co-IP, shRNA/adenoviral overexpression, cytokine ELISA, NFkB/c-Jun blots, endosomal fractionation in BMDMs/PBMCs

    PMID:30471852

    Open questions at the time
    • Single lab, Co-IP-based interaction
    • Direct versus adaptor-mediated TLR4 binding not defined
  13. 2022 High

    Established cargo-specific recycling control by RAB21, showing it preserves GLUT1 surface recycling via retromer/SNX27 and that its loss activates AMPK-ULK1 autophagy.

    Evidence siRNA, GLUT1 trafficking and glucose uptake assays, AMPK-ULK1 blots, SNX27/retromer IF, in vivo tumor growth

    PMID:35993307

    Open questions at the time
    • Mechanism of RAB21 in retromer tubule fission not molecularly defined
    • Selectivity over other retromer cargo only partially mapped
  14. 2023 High

    Distinguished RAB21 from Rab5 as a dedicated regulator of caveolin-mediated endocytosis, controlling caveolin-1 levels and neurite pruning.

    Evidence siRNA, IF co-localization, live imaging, caveolin-1 level assays, neurite pruning assays in cortical neurons

    PMID:36683567

    Open questions at the time
    • How RAB21 selects caveolar over clathrin routes mechanistically unclear
    • Effectors mediating caveolin-1 trafficking unidentified
  15. 2023 Medium

    Showed RAB21 controls neuronal surface APP via endocytic trafficking, governing cortical neuron differentiation and migration in vivo.

    Evidence In utero electroporation loss-of-function, APP surface biotinylation, confocal imaging, cortical migration analysis

    PMID:37534523

    Open questions at the time
    • Direct APP-RAB21 relationship versus indirect surface effect not separated
    • Limited orthogonal validation
  16. 2025 High

    Defined RAB21 as a broad regulator of the macrophage surfaceome controlling FcgR surface levels and antibody-dependent phagocytosis.

    Evidence Genome-wide CRISPR screen, CRISPR KO validation, surface immunophenotyping, surfaceome proteomics, phagocytosis assays

    PMID:40580479

    Open questions at the time
    • Whether surfaceome changes reflect a single trafficking step or pleiotropic effects unresolved
    • Direct cargo among surface proteins not enumerated
  17. 2025 Medium

    Extended the VARP-RAB21-VAMP7 axis to autophagic ATP secretion and autophagosome biogenesis, ordering RAB21 between VARP and VAMP7.

    Evidence CRISPR KO of RAB21/VAMP7/VARP, inactive-RAB21 overexpression, ATP secretion assays, LC3-II/DFCP1 quantification

    PMID:40395984

    Open questions at the time
    • Single lab, limited replication
    • Molecular step controlling amphisome formation not detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The RAB21 GAP and the molecular basis for its cargo-selective sorting across diverse pathways (integrins, GLUT1, caveolin-1, TLR4, FcgR) remain undefined.
  • No GAP identified in the corpus
  • Common adaptor/effector explaining cargo selectivity unknown
  • Structural basis of RAB21 cargo and effector recognition uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3 GO:0005215 transporter activity 1
Localization
GO:0005768 endosome 4 GO:0005764 lysosome 2
Pathway
R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2 R-HSA-1640170 Cell Cycle 1
Partners
EGFRITGA (ALPHA-INTEGRIN)MTMR13PSEN1RASA1VAMP7VAMP8VARP

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Rab21 (and Rab5) directly associate with the cytoplasmic domains of alpha-integrin chains, and Rab21 expression influences endo/exocytic trafficking of integrins. This function requires its GTP/GDP cycle and proper membrane targeting. Knockdown impairs integrin-mediated cell adhesion and motility; overexpression stimulates migration. An integrin point mutant deficient in Rab21 association failed to respond to Rab21 overexpression. Co-immunoprecipitation, siRNA knockdown, overexpression, integrin mutant rescue experiments, cell adhesion and migration assays The Journal of cell biology High 16754960
2004 Rab21 localizes predominantly to the early endocytic pathway on vesicles containing EEA1, transferrin receptor and internalised ligands. GTP-hydrolysis deficient mutant (Q78L) labels enlarged early endosomes; GDP-binding mutant (T33N) labels tubular reticular structures and the trans-Golgi network. Cells expressing T33N show defects in endocytosis of transferrin and EGF and fail to deliver EGF to late endosomes/lysosomes. Rab21 colocalizes extensively with early endocytic Rabs (Rab4, Rab5, Rab17, Rab22) but not late endosomal Rabs. GFP-fusion confocal fluorescence microscopy, ultrastructural studies, GTP/GDP mutant transfection, endocytosis assays (transferrin, EGF) Journal of cell science High 15561770
2006 Varp (VPS9-ankyrin-repeat protein) is a guanine nucleotide exchange factor (GEF) for Rab21. Varp interacts preferentially with GDP-bound Rab21 and has much stronger GEF activity toward Rab21 than Rab5. RNAi-mediated depletion of Varp disrupts Rab21 activity in HeLa cells. Ectopically expressed Varp localizes to early endosomes and causes enlargement of early and late endosomes. Both VPS9 domain and ankyrin repeats are required for endosomal localization and Varp activity in vivo. GEF activity assay (in vitro nucleotide exchange), co-immunoprecipitation with GDP/GTP-bound Rab21 mutants, RNAi knockdown, overexpression, confocal microscopy Journal of cell science High 16525121
2008 Rab21-regulated integrin trafficking to and from the cleavage furrow is required for successful cytokinesis. Rab21 activity, integrin-Rab21 association, and integrin endocytosis are all necessary for normal cytokinesis; failure of integrin-mediated adhesion at the cleavage furrow impairs cell division and leads to multinucleate cells. Chromosomal deletion and loss of Rab21 in human cancer results in multinucleate cell accumulation, rescued by Rab21 reintroduction. siRNA knockdown, dominant-negative and constitutively active Rab21 mutants, integrin-binding mutants, live imaging, rescue experiments, analysis of cancer cell lines with Rab21 deletion Developmental cell High 18804435
2009 Varp (as a Rab21 GEF) interacts with TI-VAMP/VAMP7 through a specific interacting domain (ID). Varp, TI-VAMP and Rab21 co-localize in the perinuclear region and in transport vesicles in neurite shafts of differentiating hippocampal neurons. Silencing Varp or expressing dominant-negative constructs impairs neurite growth. The GTP-hydrolysis-deficient Rab21 mutant enhances neurite growth, establishing that Varp promotes neurite growth via its GEF activity on Rab21 and its interaction with TI-VAMP. Co-immunoprecipitation, RNAi knockdown, dominant-negative/constitutively active Rab21 mutants, confocal co-localization, neurite growth assays in hippocampal neurons EMBO reports High 19745841
2011 p120RasGAP (RASA1) competes with Rab21 for binding to the cytoplasmic domain of integrin alpha-subunits via its GAP domain. p120RasGAP binding to endocytosed integrins facilitates exit from Rab21- and EEA1-positive endosomes, driving integrin recycling to the plasma membrane. Silencing p120RasGAP attenuates integrin recycling and augments cell motility. Co-immunoprecipitation, siRNA knockdown, integrin recycling assays, cell motility assays The Journal of cell biology High 21768288
2011 In melanocytes, the Rab21-GEF activity (VPS9 domain) of Varp, but not its Rab32/38 effector function, is required for forskolin-induced dendrite formation. Knockdown-rescue experiments showed that VPS9 domain mutants of Varp (D310A, Y350A) and VAMP7-binding-deficient mutants failed to support dendrite formation, while Rab32/38-binding-deficient Varp fully rescued the phenotype. siRNA knockdown, rescue with wild-type and domain mutant constructs, fluorescence microscopy, melanocyte dendrite formation assay Molecular biology of the cell High 22171327
2012 Drosophila MTM pseudophosphatase Sbf functions as a GEF that promotes Rab21 GTPase activation associated with PI(3)P endosomes. Sbf coordinates PI(3)P turnover and Rab21 activation in an endosomal pathway that controls macrophage protrusion formation. Sbf, Mtm (recruited by Sbf), and Rab21 function together with Rab11-mediated trafficking to control macrophage remodeling. GEF activity assay, RNAi knockdown, genetic epistasis, live imaging, PI(3)P biosensors, co-immunoprecipitation in Drosophila macrophages Molecular biology of the cell High 22648168
2015 Sbf/MTMR13 is a GEF for Rab21 (conserved between Drosophila and mammals). Starvation induces Sbf/MTMR13 GEF activity and RAB21 activation, and their induced binding to VAMP8. MTMR13 is required for RAB21 activation, VAMP8 interaction, and VAMP8 endolysosomal trafficking. Depletion of Sbf/MTMR13 or Rab21 blocked endolysosomal trafficking of VAMP8, a SNARE required for autophagosome-lysosome fusion, impairing starvation-induced autophagy. RNAi depletion, RAB21 activity assay (GST-effector pulldown), co-immunoprecipitation, endolysosomal trafficking assays, autophagy flux assays EMBO reports High 25648148
2009 Rab21 is a transient component of macropinosomes in M-CSF-stimulated macrophages. GTP-bound Rab21 (Q78L) is recruited to macropinosomes; GDP-bound mutant (T33N) is not recruited, indicating GTP binding is required. Rab21 recruitment lags behind Rab5 and precedes Rab7 and Lamp1 accumulation, positioning Rab21 at early-to-intermediate stages of macropinosome maturation. Neither Rab21 mutant significantly affected macropinosome formation rate. Live-cell imaging of fluorescent protein-fused Rab21 and mutants, co-localization with endosomal markers in RAW264 macrophages PloS one Medium 19693279
2007 PI3K inhibition (wortmannin or 3-methyladenine) induces formation of Rab21-positive tubular endosomes derived from Rab5-positive early endosomes (not late endosomes, recycling endosomes, lysosomes, or TGN). Tubule formation requires microtubules and correlates with loss of PI(3)P. Loss of PI(3)P from class III PI3K inhibition triggers morphological change of Rab21-positive early endosomes from vesicular to tubular form. Time-lapse fluorescence microscopy, PI3K inhibitor treatment, tandem FYVE domain PI(3)P reporter, co-expression of organelle markers, microtubule depolymerization Experimental cell research Medium 18162182
2009 Rab21 is required for CAF (carcinoma-associated fibroblast)-promoted matrix remodelling and cancer cell invasion. Rab21 enables accumulation of integrin alpha5 at the plasma membrane and subsequent force-mediated matrix remodeling by fibroblasts. Chemical screen, siRNA knockdown, organotypic invasion assays, integrin localization by immunofluorescence British journal of cancer Medium 19953096
2012 Rab21 interacts directly with EGFR (by co-immunoprecipitation) and enhances EGFR degradation by accelerating its internalization in both EGF-independent and EGF-dependent manners. Overexpression of Rab21 attenuates EGF-mediated MAPK signaling by inducing EGFR degradation. Co-immunoprecipitation, transient overexpression, EGFR degradation assays, MAPK signaling (western blot) in HEK293T and HeLa cells Biochemical and biophysical research communications Medium 22525675
2005 Two LIM domain proteins, LimF and ChLim, interact with each other and with GTP-bound Rab21 to regulate phagocytosis in Dictyostelium. LimF is required for Rab21-GTP function; ChLim antagonizes the activating function of Rab21-GTP. Constitutively active Rab21 increases phagocytosis rate; dominant-negative Rab21 inhibits it. LimF and ChLim localize to the phagocytic cup and phagolysosomal vesicles. Genetic overexpression and knockout, constitutively active and dominant-negative Rab21 mutants, double-mutant epistasis, phagocytosis rate assays, co-localization by fluorescence microscopy in Dictyostelium The EMBO journal Medium 15962002
2017 PKN1 phosphorylates RPH3A, which enhances binding of RPH3A to GTP-bound RAB21. This PKN1-RPH3A-RAB21 interaction is important for polarized localization of RAB21 and RPH3A in neutrophils, leading to PIP5K1C90 polarization. Loss of PKN1 or RPH3A impairs neutrophil integrin activation, adhesion to endothelial cells, and tissue infiltration. Myeloid-specific PKN1 loss decreases tissue injury in renal ischemia-reperfusion. Kinase phosphorylation assay, co-immunoprecipitation, genetic knockout (myeloid-specific PKN1 KO), neutrophil adhesion/migration assays, in vivo ischemia-reperfusion model Cell reports High 28636945
2017 Rab21 interacts with Presenilin 1 (PS1, the catalytic subunit of gamma-secretase) as validated by reciprocal Co-IP and immunofluorescence. Rab21 overexpression enhances Abeta generation while Rab21 silencing reduces Abeta accumulation, due to changes in gamma-secretase activity (not alpha- or beta-secretase). Rab21 promotes PS1 endocytosis and translocation from early endosome to late endosome/lysosome without affecting gamma-secretase complex synthesis or metabolism. Co-IP coupled with mass spectrometry, reciprocal Co-IP, immunofluorescence, overexpression and siRNA knockdown, Abeta ELISA, secretase activity assays, subcellular fractionation Molecular neurobiology High 28547526
2018 LPS induces association between TLR4 and Rab21, and promotes endosomal translocation of TLR4 in macrophages and monocytes. Rab21 knockdown inhibits LPS-induced TLR4 endosomal trafficking and downstream c-Jun and NFκB activation, reducing pro-inflammatory cytokine production (IL-1β, IL-6, TNF-α). Rab21 overexpression potentiates these responses. Co-immunoprecipitation, shRNA stable knockdown and adenoviral overexpression, cytokine ELISA, NFκB/c-Jun activation (western blot), endosomal fractionation in BMDMs and human PBMCs Biochemical and biophysical research communications Medium 30471852
2022 RAB21 depletion mis-sorts the glucose transporter SLC2A1/GLUT1 to lysosomes rather than recycling it, reducing glucose uptake and activating the AMPK-ULK1 pathway to increase autophagic flux. RAB21 depletion causes accumulation of the SNX27-containing retromer complex on enlarged endosomes, consistent with a role in fission of retromer-decorated endosomal tubules. RAB21 depletion does not affect retrograde transport of IGF2R or WLS from endosomes to TGN. siRNA knockdown, GLUT1 trafficking assays, glucose uptake assay, AMPK-ULK1 pathway western blotting, SNX27/retromer localization by immunofluorescence, in vivo tumor growth assay Autophagy High 35993307
2000 In non-polarized Caco-2 cells, Rab21 shows an ER-like distribution; in polarized Caco-2 cells and in human jejunal epithelial cells in vivo, Rab21 is localized to apically located vesicle-like structures, suggesting a role in apical vesicular transport in polarized intestinal epithelial cells. Generation and characterization of polyclonal anti-Rab21 antibodies, immunofluorescence of polarized and non-polarized Caco-2 cells, immunohistochemistry on human jejunal tissue European journal of cell biology Medium 10887961
2022 Rab21 protein is degraded by both the ubiquitin-proteasome pathway and the autophagy-lysosome pathway. Ubiquitinated Rab21 is increased in AD model mice but total protein level is maintained, suggesting parallel degradation pathways maintain homeostasis. Rab21 overexpression increases expression of genes involved in the autophagy-lysosome pathway. Proteasome inhibitor treatment, autophagy inhibitor treatment, ubiquitination assays, western blot in AD model mice and cell lines International journal of molecular sciences Medium 35163051
2023 Rab21 loss of function increases membrane-exposed APP (amyloid precursor protein) levels on neuronal cell surfaces, resulting in impaired cortical neuronal differentiation and migration in vivo. This defines a pathway where Rab21 controls cortical neuron migration by regulating endocytic trafficking of APP to control its surface levels. In utero electroporation for Rab21 loss-of-function, APP surface biotinylation assay, confocal imaging, cortical migration analysis in mouse brain sections Journal of neurochemistry Medium 37534523
2023 Rab21 and Rab5 localize to distinct populations of early endosomes in cortical neurons and preferentially regulate caveolin- and clathrin-mediated endocytic pathways, respectively. Suppression of Rab21 (but not Rab5) results in decreased plasma membrane localization and total levels of caveolin-1, impairing immature neurite pruning. This defines Rab21 as a specific regulator of caveolin-mediated endocytosis parallel to Rab5-mediated clathrin endocytosis. siRNA knockdown, immunofluorescence co-localization, live imaging, caveolin-1 protein level assays, neurite pruning assays in cortical neurons EMBO reports High 36683567
2025 RAB21 interacts with the tethering protein EEA1, and Rab21 overexpression rescues defects in EEA1 localization and endosomal size caused by PI3P depletion or Rab5 inhibition. Modulation of Rab5 or Rab21 dominant-negative mutant binding to Rabex-5 supports a competition model wherein Rab5 and Rab21 compete for activation by Rabex-5, with Rab21 possibly having higher affinity for Rabex-5 in vivo. Co-immunoprecipitation, overexpression of wild-type and dominant-negative mutants, PI3P depletion (pharmacological), immunofluorescence of EEA1 and endosomal markers, dominant-negative competition assays Frontiers in cell and developmental biology Medium 40519268
2025 EPLINα localizes to early endosomes in an actin-dependent manner, where it interacts with Rab21 at Rab21-containing endosomes. This supports β1-integrin recycling and cell migration. Coronin 1C was identified as an EPLIN-proximal protein that also localizes at Rab21-containing endosomes and controls integrin recycling downstream of EPLINα. Proximity biotinylation (BioID), co-localization immunofluorescence, siRNA knockdown, integrin recycling assays, cell migration assays Developmental cell Medium 40669465
2022 Rab21 depletion in Drosophila intestinal enterocytes leads to intestinal morphological abnormalities, deregulated cellular equilibrium with increased mitotic cells and cell death, activation of Yorkie signaling driving compensatory proliferation, and inflammation. Rab21 knockdown-induced hyperplasia is rescued by inhibition of EGFR signaling. Rab21 depletion affects levels of apolipoprotein ApoLpp and trehalose transporter Tret1-1, indicating roles in lipid and carbohydrate homeostasis. Drosophila tissue-specific RNAi, RNAi epistasis screen, immunofluorescence, EGFR pathway inhibition rescue, quantitative proteomics Molecular biology of the cell Medium 35171715
2025 RAB21 and its GEF VARP are required for starvation-induced autophagic ATP secretion. Constitutively inactive RAB21 inhibits ATP secretion. RAB21 overexpression rescues ATP secretion in RAB21 KO but not VAMP7 or VARP KO cells, placing RAB21 downstream of VARP and upstream of VAMP7 in this pathway. RAB21 plays a positive role in autophagosome biogenesis, controlling the number of LC3-II- and DFCP1-positive structures upon starvation. CRISPR KO of RAB21, VAMP7, and VARP; constitutively inactive RAB21 overexpression; ATP secretion assays; LC3-II and DFCP1 quantification by immunofluorescence; co-localization imaging Autophagy reports Medium 40395984
2025 RAB21 is a general regulator of macrophage surface protein expression. RAB21 inactivation reduces Fc gamma receptor (FcγR) expression at the cell surface, leading to decreased uptake of antibody-nanoparticle conjugates and impaired phagocytosis of opsonized cells. RAB21 perturbation also broadly remodels the macrophage surfaceome, as shown by surface immunophenotyping and proteomics. Genome-wide CRISPR phenotypic screens, CRISPR KO validation, surface immunophenotyping by flow cytometry, surfaceome proteomics, phagocytosis assays Cell reports High 40580479
2013 T. brucei Rab21 (TbRab21) localizes to endosomes, partially colocalizing with TbRab5A, TbRab28, and TbVps23 (ESCRT component). TbRab21 is essential for cellular proliferation and its suppression causes partial block in lysosomal trafficking. TbRab21 knockdown decreases expression of ESCRT components and TbRab28 but does not affect TbRab5A; conversely, knockdown of TbVps23 reduces TbRab21 expression, indicating TbRab21 acts downstream of TbRab5A and in close association with the trypanosome ESCRT system. RNAi knockdown, co-localization immunofluorescence, lysosomal trafficking assays, western blot analysis of Rab and ESCRT protein levels in T. brucei Eukaryotic cell Medium 24376004

Source papers

Stage 0 corpus · 44 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of beta1-integrins. The Journal of cell biology 276 16754960
2008 Integrin trafficking regulated by Rab21 is necessary for cytokinesis. Developmental cell 154 18804435
2004 A role for the small GTPase Rab21 in the early endocytic pathway. Journal of cell science 131 15561770
2011 Competitive binding of Rab21 and p120RasGAP to integrins regulates receptor traffic and migration. The Journal of cell biology 83 21768288
2015 Starvation-induced MTMR13 and RAB21 activity regulates VAMP8 to promote autophagosome-lysosome fusion. EMBO reports 76 25648148
2009 Role of Varp, a Rab21 exchange factor and TI-VAMP/VAMP7 partner, in neurite growth. EMBO reports 76 19745841
2006 Varp is a Rab21 guanine nucleotide exchange factor and regulates endosome dynamics. Journal of cell science 76 16525121
2009 A chemical biology screen reveals a role for Rab21-mediated control of actomyosin contractility in fibroblast-driven cancer invasion. British journal of cancer 63 19953096
2012 Sbf/MTMR13 coordinates PI(3)P and Rab21 regulation in endocytic control of cellular remodeling. Molecular biology of the cell 61 22648168
2015 Small GTPase Rab21 mediates fibronectin induced actin reorganization in Entamoeba histolytica: implications in pathogen invasion. PLoS pathogens 40 25730114
2005 A Rab21/LIM-only/CH-LIM complex regulates phagocytosis via both activating and inhibitory mechanisms. The EMBO journal 39 15962002
2000 Expression of Rab small GTPases in epithelial Caco-2 cells: Rab21 is an apically located GTP-binding protein in polarised intestinal epithelial cells. European journal of cell biology 37 10887961
2022 RAB21 controls autophagy and cellular energy homeostasis by regulating retromer-mediated recycling of SLC2A1/GLUT1. Autophagy 35 35993307
2009 Dynamic changes in the spatiotemporal localization of Rab21 in live RAW264 cells during macropinocytosis. PloS one 33 19693279
2017 PKN1 Directs Polarized RAB21 Vesicle Trafficking via RPH3A and Is Important for Neutrophil Adhesion and Ischemia-Reperfusion Injury. Cell reports 30 28636945
2011 The Rab21-GEF activity of Varp, but not its Rab32/38 effector function, is required for dendrite formation in melanocytes. Molecular biology of the cell 30 22171327
2017 Knockdown of Rab21 inhibits proliferation and induces apoptosis in human glioma cells. Cellular & molecular biology letters 23 29270202
2018 Requirement of Rab21 in LPS-induced TLR4 signaling and pro-inflammatory responses in macrophages and monocytes. Biochemical and biophysical research communications 22 30471852
2012 Rab21 attenuates EGF-mediated MAPK signaling through enhancing EGFR internalization and degradation. Biochemical and biophysical research communications 19 22525675
2020 Long Non-Coding RNA GAS5 Suppresses Tumor Progression and Enhances the Radiosensitivity of Prostate Cancer Through the miR-320a/RAB21 Axis. Cancer management and research 16 33061579
2015 Lpg0393 of Legionella pneumophila is a guanine-nucleotide exchange factor for Rab5, Rab21 and Rab22. PloS one 16 25821953
2023 Rab21 regulates caveolin-1-mediated endocytic trafficking to promote immature neurite pruning. EMBO reports 15 36683567
2021 CircRNA hsa_circ_0030018 regulates the development of glioma via regulating the miR-1297/RAB21 axis. Neoplasma 14 33440987
2007 Characterization of Rab21-positive tubular endosomes induced by PI3K inhibitors. Experimental cell research 14 18162182
2020 Modulation of ABCG2 surface expression by Rab5 and Rab21 to overcome multidrug resistance in cancer cells. Xenobiotica; the fate of foreign compounds in biological systems 12 31928387
2017 Rab21, a Novel PS1 Interactor, Regulates γ-Secretase Activity via PS1 Subcellular Distribution. Molecular neurobiology 12 28547526
2013 The ancient small GTPase Rab21 functions in intermediate endocytic steps in trypanosomes. Eukaryotic cell 12 24376004
2024 Tumor-Derived RAB21+ABHD12+ sEVs Drive the Premetastatic Microenvironment in the Lung. Cancer immunology research 11 38215051
2023 Diallyl Trisulfide, a Major Bioactive Constituent of Garlic, Promotes Colonic Mucosal Healing in Ulcerative Colitis through Accelerating Focal Adhesion Assembly and Consequent Epithelial Cell Migration via the Rab21-Integrin β1-Fak Pathway. Molecular nutrition & food research 9 36938915
2022 Rab21 Protein Is Degraded by Both the Ubiquitin-Proteasome Pathway and the Autophagy-Lysosome Pathway. International journal of molecular sciences 8 35163051
2022 Circular RNA Circ_0008043 promotes the proliferation and metastasis of hepatocellular carcinoma cells by regulating the microRNA (miR)-326/RAB21 axis. Bioengineered 7 35220907
2022 Rab21 in enterocytes participates in intestinal epithelium maintenance. Molecular biology of the cell 6 35171715
2025 EPLINα controls integrin recycling from Rab21 endosomes to drive breast cancer cell migration. Developmental cell 5 40669465
2016 RAB21 Activity Assay Using GST-fused APPL1. Bio-protocol 3 28251173
2025 A new role of RAB21 and VARP in autophagy and autophagic exocytosis of ATP. Autophagy reports 2 40395984
2025 Phenotypic screens for SIRPA expression reveal RAB21 as a general regulator of macrophage surface identity. Cell reports 2 40580479
2023 The Regulatory Mechanism of Rab21 in Human Diseases. Molecular neurobiology 2 37369821
2018 Atypical Switch-I Arginine plays a catalytic role in GTP hydrolysis by Rab21 from Entamoeba histolytica. Biochemical and biophysical research communications 2 30454703
2025 Rab21 recruits EEA1 and competes with Rab5 for Rabex-5 activation. Frontiers in cell and developmental biology 1 40519268
2023 The GTPase Rab21 is required for neuronal development and migration in the cerebral cortex. Journal of neurochemistry 1 37534523
2007 [Multiadaptor 4.1 and RanBP9 protein family members as putative interaction partners for VARP, a Rab21 GTPase guanine nucleotide exchange factor]. Molekuliarnaia biologiia 1 18318119
2026 Case Report: Pediatric AML with TBC1D15::RAB21 fusion and FLT3-ITD/NPM1 co-mutation: diagnostic pitfalls in morphologic mimicry of acute promyelocytic leukemia. Frontiers in oncology 0 41607534
2025 Rab21-Targeted Nano Drug Delivery System-Based FFPG for Efficient Paclitaxel Delivery to Inhibit Lung Cancer Progression. Pharmaceutics 0 39861741
2025 Proteomics analysis reveals elevated RAB21 in serum-derived extracellular vesicles from patients with follicular thyroid carcinoma. Oncology letters 0 40740986

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